Fetal akinesia deformation sequence with pontocerebellar hypoplasia, and migration and gyration defects.

Fetal akinesia deformation sequence (FADS), or Pena-Shokeir phenotype is a constellation of deformational changes resulting from decreased or absent fetal movement, and include arthrogryposis, and craniofacial and central nervous system anomalies. We report an autopsy case of a 36-6/7week female neonate with a normal female karyotype and chromosome microarray demonstrating findings consistent with FADS. We provide a detailed examination of the severe and complex central nervous system abnormalities, including marked pontocerebellar hypoplasia and cortical and cerebellar migration and gyration defects.

Endogenous panophthalmitis: A case series.

Purpose: - Two rare and unusual cases of endogenous panophthalmitis from are presented with mechanisms for infection explored. - The first patient had history of intravenous drug use (IVDU) without any medical implants. The second patient, in addition to IVDU, had a history of end-stage renal disease with upper extremity arteriovenous fistula graft infection from confirmed by wound culture.

Neuroepithelial Cyst of the Optic Nerve in a Newborn.

Cystic lesions of the optic nerve are uncommon findings that have been associated with neoplasms, systemic disorders, or described as idiopathic. They have been described in a wide range of ages, with few congenital cysts having been described in infants. Surgical excision of these lesions may lead to significant morbidity as previously reported cases often involved transection of the optic nerve.

Lethal neonatal meningoencephalitis caused by multi-drug resistant, highly virulent Escherichia coli.

Neonatal meningitis is a rare but devastating condition. Multi-drug resistant (MDR) bacteria represent a substantial global health risk. This study reports on an aggressive case of lethal neonatal meningitis due to a MDR Escherichia coli (serotype O75:H5:K1).

Hybrid Neurofibroma/Schwannoma of the Supraorbital Nerve: Clinicopathologic Correlation of a Rare Tumor.

Benign peripheral nerve sheath tumors such as schwannoma and neurofibroma have long been considered distinct entities. Recently, hybrid tumors demonstrating combined morphological features of neurofibroma and schwannoma have been described, primarily in dermal locations. Only 1 case of hybrid peripheral nerve sheath tumor of the orbit has been reported in the literature.

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse.

Partial mGlu₅ Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse.

Papillary tumor of the pineal region with synchronous suprasellar focus and novel cytogenetic features.

Papillary tumor of the pineal region (PTPR) is an uncommon neoplasm with variable biologic behavior. Cytogenetic and molecular diagnostic studies are rare, yielding no definitive genetic signature. We report a case of PTPR with a multicentric presentation and unusual cytogenetic features.

Retinal metastasis from unknown primary: diagnosis, management, and clinicopathologic correlation.

A 75-year-old man was incidentally found to have a yellow-white retinal lesion with scattered hemorrhages. He was empirically treated elsewhere for viral retinitis without resolution and later transferred to the Vanderbilt Eye Institute, where retinal biopsy with silicone oil tamponade showed retinal metastasis. He had no prior history of cancer, and multiple systemic imaging evaluations failed to identify a primary site.

Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence.

As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure-activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4-8 or 45 other CNS receptors.

Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence.

Compounds that modulate metabotropic glutamate subtype 2 (mGlu(2)) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu(2) receptor positive allosteric modulators (PAMs). The effects of N-substitution (R(1)) and substitutions on the aryl ring (R(2)) were identified as key areas for SAR exploration (Figure 3).

Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration.

Intramedullary spinal immature teratoma: resolution of quadriplegia following resection in a 4-week-old infant.

Intramedullary spinal cord teratomas are rare entities in infants. Management of these lesions is primarily surgical, with outcome dependent on rapid surgical decompression and complete gross-total tumor resection. The lesions are typically of the mature type, with immature teratomas displaying unique pathological features.

Calmodulin interacts with the V2 vasopressin receptor: elimination of binding to the C terminus also eliminates arginine vasopressin-stimulated elevation of intracellular calcium.

To identify molecules that might contribute to V2 vasopressin receptor (V2R) trafficking or signaling, we searched for novel interacting proteins with this receptor. Preliminary data, using the V2R C terminus as bait in a yeast two-hybrid screen, revealed calmodulin as a binding partner. Because calmodulin interacts with other G protein-coupled receptors, we explored this interaction and its possible functional relevance in greater detail.

Membrane trafficking of G protein-coupled receptors.

G protein-coupled receptors (GPCRs) modulate diverse physiological and behavioral signaling pathways by virtue of changes in receptor activation and inactivation states. Functional changes in receptor properties include dynamic interactions with regulatory molecules and trafficking to various cellular compartments at various stages of the life cycle of a GPCR. This review focuses on trafficking of GPCRs to the cell surface, stabilization there, and agonist-regulated turnover.

Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation.

To understand the mechanisms of G protein-coupled receptor delivery and steady state localization, we examined the trafficking itineraries of wild type (WT) and mutant V2 vasopressin receptors (V2Rs) in polarized Madin-Darby canine kidney II (MDCK II) cells and in COS M6 cells; the mutant V2Rs represent selected alleles responsible for X-linked nephrogenic diabetes insipidus. The WT V2R is localized on the plasma membrane and mediates arginine vasopressin (AVP)-stimulated cAMP accumulation, whereas the clinically relevant V2R mutants, L292P V2R, Delta V278 V2R, and R337X V2R, are retained intracellularly, are insensitive to extracellularly added AVP, and are not processed beyond initial immature glycosylation, manifest by their endoglycosidase H sensitivity. Reduced temperature and pharmacological, but not chemical, strategies rescue mutant V2Rs to the cell surface of COS M6 cells; surface rescue of L292P V2R and R337X V2R, but not of Delta V278 V2R, parallels acquisition of AVP-stimulated cAMP production.